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Angiogenesis-Based Strategy by Hepatocyte Growth Factor for the Treatment of Ischemic Organ Diseases: From Biology to Clinical Trials

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Biochemical Basis and Therapeutic Implications of Angiogenesis

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 6))

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Abstract

Hepatocyte growth factor (HGF) was originally identified as a potent mitogen of hepatocytes in 1980s. HGF induces mitogenic, motogenic and morphogenic activities in epithelial cells through tyrosine phosphorylation of its receptor, c-Met. HGF-c-Met axis is necessary for embryogenesis, organogenesis and tissue repair of almost epithelial organs. Indeed, a loss in HGF-c-Met signaling pathways leads to organ damage and dysfunction during acute and chronic diseases. In the early 1990s’, HGF was shown to be an angiogenic regulator via direct effects on endothelial cells (ECs). HGF plays an important part for vascular branching tubular formation via mitogenic, motogenic and morphogenic activities. HGF stabilizes endothelial barrier function via Rac1-dependent cascades. HGF is an anti-inflammatory ligand through inhibiting NF-κB activation in ECs. HGF protects ECs from injurious stresses. However, local HGF production is impaired due to cylic AMP depletion under an ischemic condition. In contrast, c-Met expression is up-regulated, in response to a local hypoxia. When HGF is exogenously injected to hypoxic regions, angiogenic regeneration is induced, associated with an increase in blood flow. This is a rationale why HGF supplemental therapy improves ischemic organ diseases, such as peripheral arterial disease (PAD) and cardial arterial disease (CAD) at least in animal models. Now, clinical trials are ongoing worldwide to determine an optimal condition of HGF supplemental therapy for the treatments of PAD and CAD. In this review, a therapeutic potential of HGF will be discussed, with a focus on biological mechanisms and preclinical or clinical outcomes during ischemic organ diseases.

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Correspondence to Shinya Mizuno DVM, PhD .

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Mizuno, S. (2017). Angiogenesis-Based Strategy by Hepatocyte Growth Factor for the Treatment of Ischemic Organ Diseases: From Biology to Clinical Trials. In: Mehta, J., Mathur, P., Dhalla, N. (eds) Biochemical Basis and Therapeutic Implications of Angiogenesis. Advances in Biochemistry in Health and Disease, vol 6. Springer, Cham. https://doi.org/10.1007/978-3-319-61115-0_6

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